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Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions. We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level. We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI. Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.

Key Clinical Message BI‐ALCL is a rare CD30+ T‐cell malignancy, which is known to complicate textured breast implants. The CD30‐targeting immunoconjugate, brentuximab vedotin, has been suggested for invasive BI‐ALCL; however, its efficacy for unresectable BI‐ALCL has not been demonstrated. We present a case of unresectable BI‐ALCL, which was successfully treated with brentuximab vedotin.

Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions.We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level.We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI.Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.

Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cyclic adenosine and guanosine mono-phosphate (cAMP and cGMP, respectively). Increased cAMP signaling has been associated with adrenocortical tumors and Cushing syndrome. Genetic defects in phosphodiesterase 11A (PDE11A) may lead to increased cAMP signaling and are found to predispose to the development of adrenocortical, prostate, and testicular tumors. A previously reported Pde11a knockout (Pde11a(−/−)) mouse line was studied and found to express PDE11A mRNA and protein still, albeit at reduced levels; functional studies in various tissues showed increased cAMP levels and reduced PDE11A activity. Since patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line. Indeed, Pde11a(−/−) mice failed to suppress corticosterone secretion in response to low dose dexamethasone, and in addition exhibited adrenal subcapsular hyperplasia with predominant fetal-like features in the inner adrenal cortex, mimicking other mouse models of increased cAMP signaling in the adrenal cortex. We conclude that a previously reported Pde11a(−/−) mouse showed continuing expression and function of PDE11A in most tissues. Nevertheless, Pde11a partial inactivation in mice led to an adrenocortical phenotype that was consistent with what we see in patients with PDE11A haploinsufficiency.

BACKGROUND: Psychiatric symptoms typically cut across traditional diagnostic categories. In order to devise individually tailored treatments, there is a need to identify the basic mechanisms that underlie these symptoms. Behavioral economics provides a framework for studying these mechanisms at the behavioral level. Here, we utilized this framework to examine a widely ignored aspect of trauma-related symptomatology-individual uncertainty attitudes-in combat veterans with and without posttraumatic stress disorder (PTSD). METHODS: Fifty-seven combat veterans, including 30 with PTSD and 27 without PTSD, completed a risk and ambiguity decision-making task that characterizes individual uncertainty attitudes, distinguishing between attitudes toward uncertain outcomes with known ("risk") and unknown ("ambiguity") probabilities, and between attitudes toward uncertain gains and uncertain losses. Participants' choices were used to estimate risk and ambiguity attitudes in the gain and loss domains. RESULTS: Veterans with PTSD were more averse to ambiguity, but not risk, compared to veterans without PTSD, when making choices between possible losses, but not gains. The degree of aversion was associated with anxious arousal (e.g., hypervigilance) symptoms, as well as with the degree of combat exposure. Moreover, ambiguity attitudes fully mediated the association between combat exposure and anxious arousal symptoms. CONCLUSIONS: These results provide a foundation for prospective studies of the causal association between ambiguity attitudes and trauma-related symptoms, as well as etiologic studies of the neural underpinnings of these behavioral outcomes. More generally, these results demonstrate the potential of neuroeconomic and behavioral economic techniques for devising objective and incentive-compatible diagnostic tools, and investigating the etiology of psychiatric disorders.© 2016 Wiley Periodicals, Inc. Language: en

ObjectiveWe have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype–phenotype correlation of theirPRKACAamplification.DesignThis study is a case series.MethodsMolecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.ResultsReinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entirePRKACAgene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient,PRKACAtriplication was associated with a more severe phenotype.ConclusionsConstitutional chromosomalPRKACAgene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occurde novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication.PRKACAamplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.

Adolescents engage in a wide range of risky behaviors that their older peers shun, and at an enormous cost. Despite being older, stronger, and healthier than children, adolescents face twice the risk of mortality and morbidity faced by their younger peers. Are adolescents really risk-seekers or does some richer underlying preference drive their love of the uncertain? To answer that question, we used standard experimental economic methods to assess the attitudes of 65 individuals ranging in age from 12 to 50 toward risk and ambiguity. Perhaps surprisingly, we found that adolescents were, if anything, more averse to clearly stated risks than their older peers. What distinguished adolescents was their willingness to accept ambiguous conditions—situations in which the likelihood of winning and losing is unknown. Though adults find ambiguous monetary lotteries undesirable, adolescents find them tolerable. This finding suggests that the higher level of risk-taking observed among adolescents may reflect a higher tolerance for the unknown. Biologically, such a tolerance may make sense, because it would allow young organisms to take better advantage of learning opportunities; it also suggests that policies that seek to inform adolescents of the risks, costs, and benefits of unexperienced dangerous behaviors may be effective and, when appropriate, could be used to complement policies that limit their experiences.

KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.

Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. Objective: We studied the genotype-phenotype correlation in CNC. Design and Setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did ...

Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets.

Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney-Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney-Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney-Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney-Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney-Stratakis syndrome-and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT-or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney-Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted. Modern Pathology (2011) 24, 147-151; doi:10.1038/modpathol.2010.185; published online 1 October 2010

Resumen La presente revision de la literatura cientifica aporta, en primer lugar y a modo de introduccion, informacion sobre la educacion terapeutica de la persona con diabetes y sus famliares, asi como el concepto de educacion dietetica nutricional. En segundo lugar, revisa el enfoque actual del tratamiento de la diabetes mellitus tipo 1 sea con terapia con multiples dosis de insulina (MDI) o con infusion subcutanea continua de insulina (ISCI), y su relacion con el plan de alimentacion mas liberalizado, ya que permiten un mejor ajuste de la dosis de insulina preprandial segun la ingesta de hidratos de carbono (HC); tambien se aportan aspectos relacionados con la adherencia al seguimiento dietetico. Finalmente, en tercer lugar, se exponen las bases y caracteristicas de la terapia ISCI, el aprendizaje especifico que han de realizar las personas con diabetes y sus familiares, centrado basicamente en los aspectos diferenciales relacionados con el plan de alimentacion respecto a las MDI. La terapia ISCI puede ofrecer mas flexibilidad dietetica que cualquier otra modalidad de tratamiento, aunque para optimizar las prestaciones del infusor, el paciente no solo ha de aprender a estimar el aporte de HC, sino tambien otros nutrientes, como el aporte de grasa o fibra, que pueden interferir en su absorcion.

A multicenter cross-sectional study showed prevalence appears to be increasing., This 2-year cross-sectional evaluation of nontuberculous mycobacterial (NTM) infections involved all Israeli medical centers that treat cystic fibrosis patients. The study comprised 186 patients whose sputum was analyzed for NTM. The prevalence of NTM isolates was 22.6%, and 6.5% and 10.8% of the patients fulfilled the 1997 and 2007 American Thoracic Society criteria for NTM lung disease, respectively. Mycobacterium simiae (40.5%), M. abscessus (31.0%), and M. avium complex (14.3%) were the most prevalent. Presence of Aspergillus spp. in sputum and the number of sputum specimens processed for mycobacteria were the most significant predictors for isolation of NTM (odds ratio [OR] = 5.14, 95% confidence interval [CI] 1.87–14.11 and OR = 1.47, 95% CI 1.17–1.85, respectively). The incidence of NTM pulmonary infections is increasing among cystic fibrosis patients, reflecting the increase in longevity of such patients as well as environmental exposure to various species of mycobacteria.

Two suicide bombings in and around Taba, Egypt, on 7 October 2004 created a complex medical and organisational situation. Since most victims were Israeli tourists, the National Emergency and Disaster Management Division handled their evacuation and treatment. This paper describes the event chronologically, as well as the organisational and management challenges confronted and applied solutions. Forty-nine emergency personnel and physicians were flown early to the disaster area to reinforce scarce local medical resources. Two hundred casualties were recorded: 32 dead and 168 injured. Eilat hospital was transformed into a triage facility. Thirty-two seriously injured patients were flown to two remote trauma centres in central Israel. Management of mass casualty incidents is difficult when local resources are inadequate. An effective response should include: rapid transportation of experienced trauma teams to the disaster zone; conversion of local medical amenities into a triage centre; and rapid evacuation of the seriously injured to higher level medical facilities.

Adults with hypoparathyroidism have significant rates of nephrocalcinosis and impaired renal function. Little is known about the impact of hypoparathyroidism treatment on renal function in children.To determine the prevalence and predictors for renal abnormalities (nephrocalcinosis and decreased estimated glomerular filtration rate [eGFR]) in children with treated hypoparathyroidism.A retrospective chart review of patients with permanent hypoparathyroidism at the Hospital for Sick Children, Toronto, between 1996 and 2013.Data of 29 patients (15 males) followed for at least 1 year with documented hypoparathyroidism were analyzed. Mean duration of follow up was 7.4 ± 5 years.The presence or absence of nephrocalcinosis as detected on ultrasound and eGFR were evaluated.Time-weighted average serum measurements were calculated for all biochemical variables. Mean total and ionized serum calcium were 8.9 ± 0.8 and 4.6 ± 0.5 mg/dL, respectively. Nephrocalcinosis was observed in 38% of the subjects, with the most significant predictors being the degree of relative hypercalcemia and hyperphosphatemia (R(2) = 0.47, P.01). Although all patients had an eGFR greater than 60, in 45% of the children, the eGRF was between 60 and 90 mL/min per 1.73 m(2). Higher calcium concentrations (r = -0.42, P = .02) and a greater proportion of time with relative hypercalcemia (r = -0.41, P = .03) were associated with lower eGFR.Our results establish that children with hypoparathyroidism treated with calcitriol and calcium supplements are at risk for nephrocalcinosis and decreased eGFR. Because hypoparathyroidism is most commonly a life-long condition, careful monitoring and management of calcium abnormalities has important future implications.

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in theIGSF1gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH).IGSF1was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenicIGSF1variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, whichin silicoanalysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with theIGSF1p.N604T variant compared with a GH-producing adenoma from a patient negative for anyIGSF1variants and with normal control pituitary tissue. TheIGSF1gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or withoutIGSF1germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

Fundamento: El uso de bombas de infusión continua de insulina (BICI) para la diabetes mellitus tipo 1 (DM1) se ha relacionado con un mejor control metabólico al compararlo con las múltiples dosis de insulina (MDI). Este mejor control puede traducirse en una disminución de las complicaciones asociadas a la DM1 y por lo tanto una reducción de los costes asociados. Sin embargo el uso de esta terapia ha quedado mermado, al menos en parte, debido a su mayor coste inicial de adquisición. El objetivo del presente estudio fue estimar las consecuencias clínicas y económicas del uso de BICI frente a MDI a través de un análisis de coste-utilidad. Métodos: Se adaptó un modelo matemático de simulación que emplea datos clínicos y económicos de ámbito nacional, para simular las consecuencias clínicas y económicas a largo plazo de un paciente con DM1. El horizonte temporal fue el de toda la vida del paciente, incluyendo sólo costes directos sanitarios, y actualizando tanto costes como beneficios a una tasa del 3% anual. Resultados: En el caso base los pacientes tratados con BICI experimentaron una ganancia de vida de 0,890 años (p

Objective To assess the effects of telecare on the results of intensive follow-up in T1D patients with poor metabolic control. Methods After initial evaluation, 40 T1D were randomised to either a Telecare (TG) or Conventional Group (CG). Patients had an intensive 6-month follow-up and helped to make decisions concerning treatment self-management. The TG had 12 appointments: 9 telematic with the GlucoBeep system + 3 ambulatory. The CG had 12 outpatient appointments. At 0, 6 (end of study) and 12 months, metabolic control, self-management and quality of life were evaluated. Cost analysis was made at study end. Results Thirty patients completed the study (16 TG, 14 CG). Intention to treat analysis included 19 TG and 16 CG. Improvement in HbA1c was similar in both groups TG: 8.4 ± 1.2%; 7.5 ± 1.4%; 7.6 ± 0.9%, p = 0.008; CG: 8.9 ± 1.3%; 7.7 ± 0.9%; 7.6 ± 0.7%, p = 0.001; with a decrease in hypoglycaemic events and improvement in self-management and quality of life. Patient costs were lower in the TG versus CG in appointment length (0.25 h versus 0.5 h). However, 30% of the diabetes team and patient appointments were longer than expected due to technical difficulties: (0.25 h versus 1 h). Conclusions Intensive telematic follow-up achieves similar results to those of intensive face-to-face follow-up with lower patient costs. However, communication technology must be improved.

Background: The primary aim was to determine the rate and nature of late postoperative complications in relation to the type of band used and the route through which it encircled the stomach in a retrospective review of postoperative complications that necessitated reoperation in 500 consecutive cases of laparoscopic adjustable gastric banding (LAGB) conducted over the past 48 months. Methods: The four study groups were: (A) Lap-Band® perigastric route, 186 cases; (B) Lap-Band® pars flaccida route 73 cases; (C) SAGB perigastric 70 cases, and (D) SAGB pars flaccida, 171 cases. There were 414 women and 86 men. The mean age was 39.2 ± 11.0 years (17–68). The mean weight was 126 kg, and mean BMI was 43.4 kg/m2 prior to operation. Results: There were 32 cases of slippage (17%) in group A and five cases (7%) in Group B (P

Objective: In a previous study, ketamine suppressed Escherichia coli-induced production of the cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNFα). In other previous studies ketamine improved survival after E. coli inoculation. However, the relationship between cytokines and survival following ketamine treatment is uncertain because no study has examined both cytokines and survival after E. coli inoculation. Methods: Rats were given E. coli (0.4×109 colony forming unit (CFU)) at time 0, followed by ketamine (50 mg/kg, n=30) or saline (n=30) at 5 min or 2 h. IL-6 and TNFα were measured in serum at 6 h, and mortality was recorded for 7 days. Results: Survival rate with ketamine was 57% (17/30) and was significantly increased compared to saline (27%, 8/30, P=0.01). IL-6 and TNFα were lower with ketamine than saline (15,197±3444 versus 30,725±4623 pg/ml [mean±S.E.M.], P=0.013 and 38.5±9.5 versus 122.5±14.0 pg/ml, P=0.001, respectively). With ketamine, IL-6 (but not TNFα) concentrations were lower in the survivors (10,900±776 pg/ml) as compared to the non-survivors (P=0.01). IL-6 in ketamine-treated survivors was not different from that in saline-treated survivors. Conclusion: We conclude that ketamine given 5 min or 2 h after induction of E. coli sepsis significantly improves survival, possibly by interfering with the inflammatory cascade (as evidenced by attenuation of cytokine production).

The purpose of this study was to investigate the pregnancy outcome of patients after bariatric surgery.A population-based study was performed that compared all pregnancies of patients with and without previous obesity operations between the years 1988 and 2002. Stratified analyses with the Mantel-Haenszel technique and a multiple logistic regression model were performed to control for confounders.Of the 159210 deliveries that were performed during the study period, 298 deliveries were to patients after bariatric operations. No significant differences regarding obstetric characteristics or pregnancy outcome were noted between the open (n=159) and laparoscopic procedures (n=139). With the use of a multivariable analysis, the following conditions were associated significantly with a previous bariatric operation: previous cesarean delivery (odds ratios, 1.4; 95% confidence interval, 1.1-2.0; P=.024), fertility treatments (odds ratios, 2.3; 95% confidence interval, 1.6-3.8; P.001), premature rupture of membranes (odds ratios, 1.9; 95% confidence interval, 1.3-2.7; P=.001), labor induction (odds ratios, 2.1; 95% confidence interval, 1.6-2.7; P.001), fetal macrosomia (birth weight,4 kg; odds ratios, 2.1; 95% confidence interval, 1.4-3.0; P.001), and obesity (odds ratios, 8.8; 95% confidence interval, 6.1-12.9; P.001). No significant differences were noted between the groups regarding other pregnancy complications such as placental abruption, placenta previa, labor dystocia, or perinatal complications (such as meconium-stained amniotic fluid, perinatal mortality, congenital malformations and low Apgar scores at 1 and 5 minutes). However, there were higher rates of cesarean delivery among the bariatric operation group (25.2% vs 12.2%; odds ratios, 2.4; 95% confidence interval, 1.9-3.1; P.001). When controlled for possible confounders (such as previous cesarean delivery, obesity, fertility treatments, premature rupture of membranes, labor induction, diabetes mellitus, hypertensive disorders and fetal macrosomia) by the Mantel-Haenszel technique, the correlation between previous bariatric surgery and cesarean delivery remained significant.Previous bariatric surgery, although an independent risk factor for cesarean delivery, is not associated with adverse perinatal outcome.

OBJECTIVE: Pregnancy in type 1 diabetes is associated with an increased risk of developing pregnancy-induced hypertension (PIH). Ambulatory blood pressure monitoring (ABPM) has been used to screen for preeclampsia in nondiabetic pregnancy. To date, there are no data regarding ABPM during pregnancy in normotensive type 1 diabetic women. This study sought to establish blood pressure (BP) profiles for pregnant type 1 diabetic women using ABPM and determine whether the BP pattern can define a population at risk for developing PIH. RESEARCH DESIGN AND METHODS: ABPM was carried out for one 24-h period during each trimester--in the first trimester between weeks 7 and 12, in the second trimester between weeks 20 and 24, and in the third trimester between weeks 30 and 34--in 22 normotensive pregnant type 1 diabetic and 10 pregnant nondiabetic women. RESULTS: The incidence of PIH was fourfold greater in type 1 diabetic women than in control subjects. Diabetic women showed higher daily diastolic BP in the third trimester compared with nondiabetic pregnant women. Diabetic women who developed PIH in the third trimester showed significantly higher BP profiles throughout gestation than those who remained normotensive. Receiver operator characteristics curves for nighttime systolic BP showed the best predictive capacity for PIH, with a cutoff > 105 mmHg (85% sensitivity and 92% specificity). CONCLUSIONS: Our study confirms the early increase of BP in patients who will develop PIH and suggests that nighttime systolic BP >105 mmHg in the second trimester is a useful predictor of PIH. ABPM may be useful in screening for PIH in pregnant diabetic women.

Background: Seroma is a well-known complication of postoperative ventral hernia (POVH) repair. It occurs during the immediate postoperative period and usually resolves with or without drainage within 4–6 weeks. The case presented herein is interesting in that a huge seroma appeared 6 months postoperatively. Ten litres were evacuated in each of two consecutive hospitalisations. The final outcome was a complete recovery with no mesh infection and no residual seroma. Of interest are the diagnosis and treatment of this unusual clinical presentation of seroma after POVH repair.

Background: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC. Setting: A tertiary care referral center was the setting for analysis of an international cohort of patients with CNC. Methods: Methods included genome-wide array analysis followed by fluorescent in situ hybridization, mRNA, and other studies as well as a retrospective analysis of clinical information and phenotype-genotype correlation. Results: We detected 17q24.2-q24.3 deletions of varying size that included the PRKAR1A gene in 11 CNC patients (of 51 tested). Quantitative PCR showed that these patients had significantly lower PRKAR1A mRNA levels. Phenotype varied but was generally severe and included manifestations that are not commonly associated with CNC, presumably due to haploinsufficiency of other genes in addition to PRKAR1A. Conclusions: A significant number (21.6%) of patients with CNC that are negative in currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing. Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and severe phenotypes who are PRKAR1A mutation-negative.

Pseudomyxoma peritonei syndrome (PMP) is a rare but fascinating entity in surgical oncology. It consists of the accumulation of mucus in the peritoneal cavity, sometimes in huge amounts, in most of the cases after rupture of an appendiceal tumor. The diagnosis and management of PMP has changed significantly in the past 15 years, with the institution of an aggressive therapeutic combination: cytoreductive surgery and intraperitoneal perioperative chemotherapy. Few reports deal with the late manifestations and complications at endstage of the disease. The cases presented here are unique in that they illustrate a late 'failure' in the perianal area in three patients with long-term PMP.

Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition to adrenocortical tumors.The aim of the study was to study the PDE11A gene in a large cohort of patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in control subjects.The PDE11A entire coding region was sequenced in 46 patients with AIMAH and 192 controls. Two variants found in AIMAH patients were transiently expressed in HEK 293 and adrenocortical H295R cells for further functional studies.The frequency of all PDE11A variants was significantly higher among patients with AIMAH (28%) compared to controls (7.2%) (P = 5 × 10(-5)). Transfection of the two PDE11A variants found in AIMAH patients only (D609N or M878V) showed that cAMP levels were higher, after forskolin stimulation, in cells transfected with the PDE11A mutants, compared to cells transfected with the wild-type PDE11A in HEK 293 cells (P0.05). Moreover, transfection with mutants PDE11A increased transcriptional activity of a cAMP-response element reporter construct compared to wild-type PDE11A in HEK 293 cells (P0.0004 for D609N and P0.003 for M878V) and in the adrenocortical H295R cells (P0.05 for D609N and M878V). In addition, analysis of cAMP levels in intact living culture cells by fluorescence resonance energy transfer probes showed increased cAMP in forskolin-treated cells transfected with PDE11A variants compared with wild-type PDE11A (P0.05).We conclude that PDE11A genetic variants may increase predisposition to AIMAH.

In the last 10 years, extensive studies showed that the cAMP pathway is deregulated in patients suffering from adrenocortical tumours, and particularly in primary pigmented nodular adrenocortical disease (PPNAD). Here we describe how evidence arising from the analysis of patients' data, mouse models and in vitro experiments, have shed light on the cAMP pathway as a central player in adrenal physiopathology. We also show how novel data generated from mouse models may point to new targets for potential therapies.

This article presents an introduction to diabetes and the problems associated with diabetes as well as scientific evidence on how to prevent or retard chronic complications diabetes causes by means of optimizing a diabetes sufferer's metabolic control. The authors make reference to one of the most important studies by The Diabetes Control and Complications Trial-DCCT which has signified a before and an after in the treatment of type 1 diabetes mellitus (DM1). Focusing on the treatment of diabetes with continuous subcutaneous insulin injection (CSII), the authors describe 1) Patients who are candidates for this treatment according to scientific associations; 2) Characteristics and functioning methods for insulin delivery systems as well as the different models of insulin delivery systems, catheters, needles and commercial inserting mechanisms presently available in Spain. The authors report on the experiences that the diabetes team at the Barcelona "Hospital Clinic" have with CSII therapy The authors describe the structure of a Therapeutic Educational Program directed at patients suffering from DM1 who are candidates for CSII therapy the process which these patients follow and the results of this program, evaluated after two years of follow-up study.

AIM To determine the 2-year efficacy of continuous subcutaneous insulin infusion (CSII) following the current established criteria for funding of a National Health Service. METHODS Longitudinal, prospective, observational unicentre study. Included in the study were 153 Type 1 diabetes (T1D) subjects, previously treated with multiple daily injections (MDI) of insulin, in whom CSII was started in accordance with the criteria for reimbursement of the Catalan National Health Service. At baseline, we recorded data on age, gender, duration of the disease, body mass index (BMI), insulin dose and indications for CSII. Glycated haemoglobin (HbA(1c)) and the frequency of hypoglycaemic events were used to assess glycaemic control. Quality of life was assessed using three different self-report questionnaires. After 24 months, these same items were remeasured in all subjects. Serious adverse events and injection-site complications were also recorded. RESULTS In 96% of subjects, CSII indication included less than optimal glycaemic control using MDI. HbA(1c) fell from 7.9 +/- 1.3 to 7.3 +/- 1.1% (P < or = 0.001) after 24 months of CSII. Insulin requirements were significantly lower at the end of follow-up (0.55 +/- 0.21 U/kg body weight) in comparison with before use of CSII (0.70 +/- 0.20, P < or = 0.001). BMI increased from 24.0 +/- 3.1 to 24.4 +/- 3.2 kg/m(2) after 24 months (P < or = 0.025). The rate of episodes of diabetic ketoacidosis per year remained unchanged. Mild and severe hypoglycaemic episodes were significantly reduced. The scores in all subsets of the Diabetes Quality-of-Life (DQoL) questionnaire significantly improved after 24 months of CSII. CONCLUSIONS CSII, commenced according to the criteria for a nationally funded clinical programme, improves glycaemic control and quality-of-life outcomes with fewer hypoglycaemic episodes in T1D subjects previously conventionally treated with MDI.

Objective To identify the characteristics of CF patients with hemoptysis in Israel and to compare clinical features and risk factors to a control group of CF patients without hemoptysis. Design Retrospective chart review. Patients All CF patients in Israel who experienced hemoptysis between 2001 and 2005 and a control group of sex- and age-matched patients with no history of hemoptysis. Results 40/440 CF patients (9.1%) experienced hemoptysis during the study period, 50% were male. Ten patients (25%) were under 13 years old at the first hemoptysis episode. Pulmonary exacerbation was the precipitating factor in 90%. Twenty three patients showed moderate or major hemoptysis. 35/40 patients responded well to conservative therapy. Bronchial artery embolization (BAE) was performed in 5 patients with no recurrence of bleed within 24 h. However all of these patients experienced recurrent hemoptysis. One patient died during the follow-up period because of end stage lung disease. Pulmonary function tests, body-mass index, coagulation tests, pancreatic status, presence of bronchiectasis, sputum cultures and genetic mutations were similar in the two groups. A high incidence (57.5%) of associated diseases including cystic fibrosis related diabetes, cirrhosis and portal hypertension, and distal intestinal obstruction syndrome was found among hemoptysis patients, compared to only 5.2% in the control group ( p Conclusions Hemoptysis, even major, did not seem to be a risk factor for mortality in our patients. A higher incidence of hemoptysis was found in our pediatric patients compared to other series. BAE shows a high immediate rate of success in controlling hemoptysis, but does not prevent future disease.

The use of continuous subcutaneous insulin infusion (CSII) for treating Type I diabetes mellitus (DM1) has been related to better metabolic control compared it to daily multiple insulin injections (DMI) and thus to a lowering of the related costs. However, this therapy is now being used to a lesser extent due, at least partially, to the higher initial cost of purchase. This study is aimed at estimating the clinical and economic consequences of using CSII as compared to DMI by means of a cost-utility analysis.A mathematical simulation model was adapted using nationwide clinical and economic data to simulate the long-term clinical and economic consequences for a DM1 patient. The time horizon was the patient's lifetime, including only direct healthcare costs and updating both costs and benefits at an annual 3% rate.In the basecase, the patients treated using CSII gained 0.890 years (p0.05) and 0.852 QALYs (p0.05). CSII treatment gives rise to an incremental average cost of 25,523 Euro (p0.05) per patient treated, which gave us an incremental cost- utility ratio of 29,947 Euro-QALY [CI 95% (29,519; 30,375)].The improvement in the glucose control among those patients treated using CSII was related to an overall lower cost in the handling of DM1 patients, which was found to have a favourable cost-utility ratio in comparison to conventional MDI treatment.

A patient developed a huge diaphragmatic hernia following laparoscopic gastric banding. Almost the entire stomach was incarcerated within the left chest. Segmental necrosis of the greater curvature of the stomach necessitated partial gastrectomy. The postoperative course was uneventful. The etiology, diagnosis and treatment of this previously undescribed complication of laparoscopic gastric banding are addressed in relation to the present case.

The objective of the study was to investigate pregnancy outcome of patients with gestational diabetes mellitus following bariatric surgery.All births to patients with gestational diabetes mellitus delivered between the years 1988 and 2002 were included in the study. A comparison between patients with and without a history of bariatric surgery was performed. Stratified analyses, using the Mantel-Haenszel technique and a multiple logistic regression model were performed to control for confounders.During the study period, there were 8014 deliveries of women with gestational diabetes mellitus. Twenty-eight were in patients following bariatric surgery. Most patients underwent restrictive (n = 26) and not malabsorptive procedures (n = 2), mainly gastric banding (n = 16). Mean levels of hemoglobin A1c and fasting glucose were comparable between the groups. No significant differences in obstetric characteristics or pregnancy outcomes were noted between the patients following bariatric surgery as compared with the comparison group, except for higher rates of fertility treatments (21.4% versus 5.5%; P.001). While controlling for nulliparity and maternal age, using a multivariable analysis, a significant association was noted between bariatric surgery and fertility treatments (odds ratios 4.7; 95% confidence interval 1.9 to 11.7; P = .001). Perinatal outcome was comparable between the groups, and no significant differences were noted with regard to complications such as perinatal mortality, congenital malformations, and low Apgar scores at 1 and 5 minutes.Previous bariatric surgery in patients with gestational diabetes mellitus is not associated with adverse perinatal outcome.

Background: Patients' nutritional habits are seldom taken in account in planning surgery for clinically severe obesity. Our proposed hypothesis is that the patient's nutritional behavior may influence the outcome of bariatric surgery. Methods: The impact of nutritional behavior on the postoperative weight-loss was evaluated before and after bariatric surgery. A 6-month prospective consecutive case study was carried out on patients undergoing a Silastic ring vertical gastroplasty (SRVG). Patients were interviewed and examined before and at 1, 3 and 6 months after surgery. Demographic and clinical data were collected from the patients' medical charts. Nutritional data collected from a self-filled questionnaire included information on hunger and satiety perception, nutritional behavior (intake, eating habits and maximum consistency of consumed food) and concomitant symptoms. Results: The sample included 69 patients: 56 were women (81%); average age was 32 years (range 18 50). Average preoperative BMI was 43.4 ′ 5.3 kg/m 2 (range 35-58). 6 months after surgery, BMI was 30.3 ′ 3.8 kg/m 2 (range 21-42). Weight loss forecast models showed a statistically significant role of factors related to: anthropometrical preoperative data, hunger perception, prevalence of oral mucosal sore, and nutritional behavior. Conclusion: The short nutrition outcomes after gastric restrictive surgery were looked at, with their impact on weight-loss success. The Eating Status concept should be part of a systematic profiling of morbidly obese patients for preoperative nutritional behavior and postoperative nutritional education, to achieve the best comprehensive treatment in regard to weight loss and quality of life.

Background: In 1999, after having performed more than 2500 open bariatric surgery procedures, we began to conduct the laparoscopic adjustable silicone gastric banding (LASGB) procedure. The purpose of this report is to present the results of our first 250 operations using this technique. Patients and methods: The 250 patients included 212 females and 38 males. The mean age was 36 years (range, 16–62). The mean BMI was 44 (range, 35–76). Patients were selected in accordance with standard criteria. The mean follow-up time was 18 months (range, 3–24). Results: Two hundred and forty procedures were completed by laparoscopy; conversion to open surgery was required in 10 cases. The mean operating time was 50 min (range, 20–145). There was no mortality. Perioperative complications included two cases of gastric perforation. Late complications included 13 cases of band slippage (5%), of which three involved penetration to the stomach, five cases of port disconnection (2%), and four cases of port site infection (1.5%). The mean weight loss at 12 months was 70% of the original excess weight. Conclusion: Most patients prefer laparoscopy as the surgical technique in the treatment of morbid obesity. Our initial experience with 250 operations confirms that this approach is as good as open surgery. The long learning curve is steep, requiring at least 100 cases to guarantee low complication rates.

In 9 of 118 patients with differentiated thyroid carcinomas, a solitary cystic lateral cervical mass simulating a branchial cleft anomaly was the sole presenting sign of the disease. These masses were nodal metastases of occult papillary adenocarcinoma of the thyroid that underwent liquefaction necrosis. Sonographically, the masses presented a complex pattern. Accordingly, it is suggested that, in patients presenting with an asymptomatic solitary lateral cystic cervical mass, the possibility of metastasis from an occult thyroid malignancy should be considered, and consent for definitive surgery should be obtained. The ultrasonic pattern of the cystic mass is of importance in the differentiation of a cavitated lymph node from a branchial cleft cyst.

An abnormally low activity of mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH), relative to the paired measurement of glutamate dehydrogenase, was found in CD3+ lymphocytes from 4 out of 14 mothers with gestational diabetes mellitus, but in none of 36 control mothers. The low m-GDH activity coincided with an abnormally high incidence of familial history for non-insulin-dependent diabetes. These findings are compatible with the view that an inherited or acquired defect of m-GDH may participate to the pathogenesis of beta-cell dysfunction in a subgroup of patients with gestational diabetes.